Accepted Manuscript

Feasibility, Safety and Efficacy of Transcutaneous Vagus Nerve Stimulation in

Chronic Tinnitus: an open Pilot Study

Peter M. Kreuzer , Michael Landgrebe , Markus Resch , Oliver Husser , Martin

Schecklmann , Florian Geisreiter , Timm B. Poeppl , Sarah J. Prasser , Goeran
Hajak , Rainer Rupprecht , Berthold Langguth
PII: S1935-861X(14)00173-9
DOI: 10.1016/j.brs.2014.05.003
Reference: BRS 549

To appear in: Brain Stimulation

Received Date: 25 March 2014

Revised Date: 7 May 2014
Accepted Date: 11 May 2014

Please cite this article as: Kreuzer PM, Landgrebe M, Resch M, Husser O, Schecklmann M, Geisreiter
F, Poeppl TB, Prasser SJ, Hajak G, Rupprecht R, Langguth B, Feasibility, Safety and Efficacy of
Transcutaneous Vagus Nerve Stimulation in Chronic Tinnitus: an open Pilot Study, Brain Stimulation
(2014), doi: 10.1016/j.brs.2014.05.003.

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 ACCEPTED MANUSCRIPT

Feasibility, Safety and Efficacy of Transcutaneous Vagus Nerve Stimulation

in Chronic Tinnitus: an open Pilot Study

Peter M. Kreuzer1, Michael Landgrebe2, Markus Resch4, Oliver Husser4, Martin

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Schecklmann1, Florian Geisreiter1, Timm B. Poeppl1, Sarah J. Prasser1, Goeran Hajak1,3,

Rainer Rupprecht1, Berthold Langguth1

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1
Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg,

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Germany
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Department of Psychiatry, Psychosomatics and Psychotherapy, kbo Lech-Mangfall-Klinik

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Agatharied, Germany
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Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Bezirksklinikum

Bamberg, Bamberg, Germany

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Department of Cardiology, Internal Medicine II, University of Regensburg, Regensburg,

Germany
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Correspondence to:

Peter Kreuzer, MD
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Department of Psychiatry and Psychotherapy, University of Regensburg

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Universitaetsstr. 84, 93053 Regensburg, Germany

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tel.: +49 941 941 1256

fax.: +49 941 941 1255

email: peter.kreuzer@medbo.de

Key words: transcutaneous vagus nerve stimulation, neuromodulation, chronic tinnitus

Financial Disclosure: The study was sponsored by CerboMed GmbH, Erlangen, Germany.
tVNS in chronic tinnitus
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Abstract

OBJECTIVES: Vagus nerve stimulation represents an established treatment strategy for

epilepsy and affective disorders. Recently, positive effects were also shown in animals and

humans with tinnitus. Here we report the results of an open pilot study exploring feasibility,

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safety and efficacy of tVNS in the treatment of chronic tinnitus.

STUDY DESIGN: Fifty patients with chronic tinnitus underwent tVNS in an open single-

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armed pilot study which was conducted in two phases applying two different stimulating

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devices (Cerbomed CM02 and NEMOS). Clinical assessment was based on Tinnitus

Questionnaire (TQ), Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI),

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WHO Quality of Life, and various numeric rating scales. Primary outcome was defined as
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change in TQ (baseline vs. final visit in week 24). The study has been registered with

clinicaltrials.gov (NCT01176734).
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RESULTS: Primary analysis indicated mean TQ reductions of 3.7 points (phase 1) and 2.8

points (phase 2) significant for the first study phase. Secondary analyses indicated a
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significant BDI reduction for phase 1 (uncorrected for multiple testing), but no further
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systematic or significant effects.

Adverse events included twitching and pressure at electrode placement site. The occurrence
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of one hospitalization because of palpations and the development of a left bundle branch
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block were considered as unrelated to the intervention. Cognitive testing revealed no

significant changes.
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CONCLUSION: Our data demonstrate the feasibility of tVNS over a period of 6 months.

There was no clinically relevant improvement of tinnitus complaints. Our data suggest tVNS

to be considered safe in patients without a history of cardiac disease.

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Introduction

Subjective tinnitus is characterized by the perception of sound or noise in the absence of a

corresponding physical sound source (1). Approximately 1% of the population reports severe

tinnitus-related impairment of daily living (2) and seek medical help (3). Severe tinnitus is

frequently associated with depressive symptoms (4), anxiety (5, 6) and insomnia (7) and is

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very difficult to treat (8).

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Electrical stimulation of the vagus nerve (VNS) is an FDA-approved therapy tool for both

refractory depression and epilepsy (9-11). Traditionally, vagus nerve stimulation has been

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performed by implantation of a neurostimulating device connected to an electrode located

along the left-sided cervical branch of the vagus nerve. In order to minimize adverse effects

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of invasive VNS a new non-invasive neurostimulating device has been developed for
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transcutaneous stimulation of the afferent auricular branch of the vagus nerve (ABVN) (t-

VNS® (12)). Two functional magnetic resonance imaging (fMRI) studies have investigated the
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effects of tVNS applied to the left tragus area in healthy adults (13, 14). Both revealed blood
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oxygen level-dependent (BOLD) signal changes mainly regarding the nucleus of the solitary
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tract (NTS) as primary projectory region and locus coeruleus and raphe nuclei as secondary

projection fields (13, 14). The brain activation pattern under tVNS clearly shares features with
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changes observed during invasive VNS (14-18). The t-VNS® device received CE approval in

2010 (CE1275).
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Various lines of argumentation support the application of VNS in chronic tinnitus.

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Tinnitus-related changes of brain activity: Several neuromodulatory techniques have been

investigated in the last years for the treatment of tinnitus (19, 20) targeting temporal and

limibic brain areas, which are also modulated by tVNS (13, 14).

Habituation: Currently available treatment options of chronic tinnitus mainly depend on

enhancement of habituation processes (for an overview see (21)). Such habituation

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processes might be enhanced by VNS as this technique has been shown to improve learning

(22) and neuroplastic processes (22-26).

Antidepressant mode of action: Invasive VNS exerts an antidepressant effect (27). Various

antidepressant approaches have shown effectiveness in patients suffering from chronic

tinnitus (28-32). It is assumed that antidepressant mechanisms influence tinnitus-related

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annoyance and handicap by modulation of emotion-regulatory brain structures.

Influence on vegetative nervous system: A relation of bothersome tinnitus and vegetative

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nervous system components has been postulated (33-35). A normalization of sympathetic

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overshooting activity should lead to a reduction in tinnitus severity as it may be observed in

relaxation techniques applied in tinnitus patients (36, 37).

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Clinical data on electrical auricular stimulation: Already back in the 1950’s, studies were
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conducted applying electrical stimulation to various auricular regions for the treatment of

tinnitus (38-56). It may be speculated that the beneficial effects might – at least in part – be
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due to an unintentional stimulation of vagal afferent fibers (57).

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Taken together, these arguments point to transcutaneous vagus nerve stimulation as a

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potentially promising approach in the treatment of chronic tinnitus.

In the present open pilot study we aimed to assess efficacy, feasibility and safety of tVNS in
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a sample of chronic tinnitus patients.

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Materials and Methods

Study design

The study was conducted in a single-armed, open-label pilot study design. Clinical visits

were scheduled at screening, baseline, week 2, week 4, week 8, week 16 (phase 1) / week

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12 (phase 2), week 24 (= end of stimulation period) with a follow-up-visit in week 28. The

study was conducted in two phases applying two different stimulating devices (CM02 in

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phase 1 and NEMOS in phase 2). Phase 1 consisted of 24 patients, phase 2 of 26 newly

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recruited patients resulting in a total of n=50 patients (for detailed information see figure 1).

Phase 1 was terminated because of two cardiac adverse events (58). After extensive

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analysis of these events, the study was continued applying an improved stimulating device
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(NEMOS in phase 2) and intensified cardiac monitoring in a different sample of patients.

Participation of phase 1 patients terminated in a premature, prompt study end visit

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after instruction by phone (on 13/08/2010) to interrupt the tVNS treatment due to two

unexpected cardiac events as described elsewhere in detail (58).

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The study was approved by the Ethics Committee of the University of Regensburg registered
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with clinicaltrials.gov (Identifier NCT01176734).

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Patient enrolment

Inclusion criteria were tinnitus with a duration of more than six months, ≥31 points in the
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tinnitus questionnaire (TQ) (59), both genders aged between 18 and 75 years, and stability of
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medication . Patients were recruited for participation in the study after presentation in the

Interdisciplinary Tinnitus Center at the University of Regensburg, Germany, or via

announcement on the website of the Tinnitus Center or the German Tinnitus League (DTL).

Exclusion criteria were objective tinnitus, participation in other tinnitus treatments within three

months before study enrolment, pregnancy, bronchial asthma in medical history, clinically

relevant comorbid diseases, abuse of drugs or alcohol, active implants (e.g. cochlea

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implants, VNS, cardiac pacemakers), dermatologic and infectious diseases affecting the

auricular region, constant all-day use of left-sided hearing aids or masking devices (part time

use in special situations (e.g. watching TV) was not regarded an exclusion criterion).

Outcome measures

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Primary outcome measure was the change in TQ (contrast baseline vs. W24 (end of

stimulation period). Clinical response was defined as a minimal reduction of 5 TQ points

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(60).

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Secondary objectives were the assessment of adverse events and safety information,

changes in TQ regarding all time points, changes in the Tinnitus Handicap Inventory (THI)

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scale (61), changes in the TBF-12-questionnaire scores (62), changes in Beck Depression
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Inventory (BDI) (63), changes in Clinical Global Impression (CGI-CHANGE), changes in

quality of life measured by WHOQoL-Bref-questionnaire ratings (64) and changes regarding

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the tinnitus perception itself, applying numeric tinnitus rating scales (tinnitus loudness,

annoyance, discomfort, distractibility, unpleasantness). Electrocardiographic tests were

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conducted at all clinical visits (Corina, GE Medical Systems Information Technology Inc.,
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Milwaukee, USA. Data were assessed according to international standards (65, 66) and

registered in a tinnitus database (67).

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tVNS neurostimulating device

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A tVNS instrument consisting of two titan electrodes connected to a wired neurostimulating

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device (CM02, Cerbomed, Erlangen, Germany) was used during phase 1 of the study, an

improved stimulating device (NEMOS, Cerbomed, Erlangen, Germany) was used during

phase 2 of the study.

The t-VNS® device offered a stimulus intensity between 0.1 and 10 mA with a stimulation

frequency of 25 Hz. Stimulation was active for 30 s, followed by a break of 180 s in phase 1

(recommended stimulation as much as possible for at least 6 hours per day) and changed to

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a 30s-on-30s-off-paradigm in phase 2 (with adjusted stimulation time of 4 hours per day).

Patients were instructed to use the stimulator only during daytime for safety reasons.

Statistical analyses

All continuous data were displayed as mean with standard deviation and were compared

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using Student’s t-test or analysis of variance when appropriate. In addition we reported the

effect sizes d for these contrasts to estimate the clinical significance according to Cohen

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(d=0.2 small, 0.5 medium, 0.8 high) (68). Statistical analyses were conducted separately for

phase 1 and phase 2. Statistical significance was assumed for a p-value <0.05.

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Unfortunately, not for all assessment time points all investigated parameters could be

compiled for every patient (leading to missing values in the tables depicted below). If not

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otherwise mentioned, all data presented in this manuscript refer to the intention-to-treat-
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sample. Missing values were replaced by the last observed value (LOCF). Sensitivity

analysis was done by means of analysis of the primary outcome for the per-protocol sample,
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i.e., patients without any serious protocol violations.

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Results

Study sample

A total number of 50 patients were enrolled in the two phases of the present study and

supplied with a tVNS stimulating device. Table 1 and table 2 depict demographic and

tinnitus-related characteristics at baseline.

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Table 1 Demographic characteristics at baseline

Continuous variables are depicted by (mean ± sd) (minimum, quartiles, maximum) (sample size). Categorial variables are

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depicted by absolute and relative frequencies.

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Table 2 Tinnitus related questionnaires and rating scales at baseline.

Variables are depicted by (mean±sd) (minimum, quartiles, maximum) (sample size).

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Dropouts
As shown in the draft of patients’ flow (figure 1), two patients were excluded from further
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participation immediately after enrolment during the combined screening/baseline visit

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because of bradycardia and arrhythmia. These two patients were not regarded as dropouts,

but categorized as “screening failures”.

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Two dropouts (phase 2) were excluded from the analysis resulting in a study sample of 48
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patients (24 patients in both study phases). One patient only participated in the

screening/baseline visit and reported a noise trauma after fireworks explosion via telephone
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call which required hospitalization and therefore was categorized as a severe adverse event.
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A second patient was withdrawn from the study after baseline visit due to cardiac

abnormalities already present before study enrolment but only diagnosed at second-look by

the cardiologist.

With 10 dropouts in phase 1 and 6 dropouts in phase 2 as well as because of missing data in

four patients (one in phase 1 and three in phase 2) the per-protocol-sample consisted of

n=13 patients in phase 1 and n=15 in phase 2.

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Figure 1 Patient samples

Primary outcome
In the intention-to-treat analysis for phase 1, TQ total score was reduced by 3.7±8.1 points

from baseline to final visit (T=2.222; df=23; p=0.036; d=0.452). Final visit of phase 1 was a

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premature study end visit due to the interruption of the study after occurrence of two

cardiac events. The study end visit in phase 1 took place 45.5 ± 21.0 days after the

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baseline visit (range: 28-70). Nine out of 24 participants were responders (37.5%).

For phase 2, TQ total score was reduced by 2.8±9.2 points from baseline to final visit

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(T=1.504; df=23; p=0.146; d=0.307). Eleven out of 24 participants were responders (45.8%)

(see Figure 2).

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Figure 2 Primary Outcome (TQ Score Sc/BL vs. end of treatment).
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In addition per-protocol (PP) analyses were conducted for sensitivity analysis. For phase 1,
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TQ total score was reduced by 2.0±8.7 points from baseline to final visit (T=0.827; df=12;
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p=0.424; d=0.230) in the pp-sample. Four out of the 13 participants were responders

(30.8%).
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For phase 2, TQ total score was reduced by 2.0±9.4 points from baseline to the final visit

(T=0.826; df=14; p=0.423; d=0.213). There were 7 responders out of the 15 participants
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(46.7%).
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Secondary outcomes

ANOVAs with the within-subjects factor time indicated no significant effects except for the TQ

total score and the BDI score for phase 1 (for details see tables 4 and 5). Post-hoc tests

indicated (near) significant amelioration of TQ scores for all visits in contrast to

screening/baseline (all ps<0.061) and significant amelioration of BDI scores of week 4 and 8

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and study end visit (phase 1) in contrast to screening/baseline (all ps<0.008) without

correction for multiple testing.

Clinical global impression showed equal numbers or even a higher number of patients with

worsening of symptoms in contrast to patients with amelioration (see supplementary

materials, table S1).

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Raw data and statistics for secondary analyses are displayed in tables 3 and 4.

T tests of neurocognitive testing (TAP) raw data of phase 2 did not show any significant

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effects for the contrast baseline vs. week 12. With respect to the contrast baseline vs. week

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24 we found a significant shortening of the median reaction time for tonic alertness and a

significant reduction of omissions during working memory for week 24 measured by t-values.

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Raw data and statistics are displayed in the supplementary table S2, relation to normative
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values is provided in supplementary table S3.

Table 3 Raw data and statistics for secondary analyses of phase 1 (mean ± sd).
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Table 4 Raw data and statistics for secondary analyses of phase 2 (mean ± sd).
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ECG recordings

The results of ECG recordings of phase 1 have been reported and discussed in detail
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elsewhere (58).
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For phase 2 (n = 24), ANOVAs with the within-subjects factor time (all time points) were

conducted regarding ECG parameters. The results are displayed in table 5.

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Notably, due to missing values of single visits only 14 of the 26 patients in study phase 2

could be included in the primary analysis of all time points.

Table 5 ANOVAS regarding ECG parameters

Therefore, in addition ANOVAs comparing pre-stimulation vs. ongoing-stimulation at

screening/baseline visit, and ANOVAs comparing screening/baseline (prestimulation

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condition) vs. W24 (end of treatment) were performed. Thus, more patients could be included

in the analysis, resulting in a significant (uncorrected level) increase of heart frequency

(scr/bL prestim. vs. W24), an effect that had not been present at analysis of all time points for

the 14 patients without missing values (for detailed information see figure S1).

Adverse events are shown in detail in table 6. It should be noted, that local feelings of

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stimulation sensation or tingling were regarded as inherent effects of the tVNS therapy and

not rated as adverse events except they were described as painful..

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Table 6 Frequency of adverse events in the whole study sample (n=50). Absolute numbers of
reported events are provided.

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Discussion

The purpose of this pilot study was to evaluate the feasibility, safety and efficacy of

transcutaneous vagus nerve stimulation (tVNS) in the treatment of chronic tinnitus.

tVNS treatment did not result in significant improvement of tinnitus complaints. Even if the

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primary outcome (TQ reduction) revealed a significant effect in phase 1, this finding

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disappeared in the per protocol analysis, was neither replicated in phase 2 nor reflected by

additional rating scales. We are well aware about the fact that all conclusions are limited by

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the lack of a control group in this pilot study. But the absence of any relevant improvement

after 6 months of tVNS enables the conclusion that the use of tVNS for the treatment of

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tinnitus cannot be recommended in its current form. Several possible reasons may account
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for the lack of a clinical effect in our study. First, the used stimulation device may have

resulted in insufficient modulation of the auricular branch of the vagal nerve. However, this
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seems rather unlikely since we observed a significant reduction of the heart rate in the

extended ECG assessment of phase 2 after 30-60 minutes of tVNS application at

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screening/baseline visit. Also a lack of compliance can be excluded, since the regular use of
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the tVNS device by the participants was demonstrated by the log files of the devices. Another

option may be that the stimulation duration of several hours/day over 24 weeks may not have
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been sufficient. This is possible, but a treatment effect which requires more hours of

stimulation / day or a longer stimulation period than 24 weeks to achieve clinically significant
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effects, provides only very limited relevance for clinical routine. The most probable
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explanation for the lack of tinnitus improvement in our study is that vagus nerve stimulation

alone is not effective for reducing tinnitus.

This notion is supported by a recent animal study (69). Whereas vagus nerve stimulation

alone had no effects on tinnitus in noise-exposed animals, vagus nerve stimulation paired

with specific auditory stimuli completely eliminated the physiological and behavioral

correlates of the phantom sound (69).

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Beneficial effects of combined auditory and vagus nerve stimulation have been confirmed by

first data from recent pilot studies in tinnitus patients using invasive (70) and trancutaneus

(71) vagus nerve stimulation. Thus the lack of a clinical effect in our study together with the

beneficial effects of combined auditory and vagus nerve stimulation in the two mentioned

clinical studies fit exactly with the result of the animal study, where the combination of

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auditory and vagal nerve stimulation was critical for the therapeutic effect (69).

With respect to the measured cardiac parameters, our preliminary data provide some hints

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for potential influences of tVNS on cardiac rhythm. At the same time the data do not

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demonstrate a clear-cut effect of tVNS on any of the tested ECG parameters. Phase 1 ECG

data and the reasons to interrupt the study temporarily were reported elsewhere already (58).

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In phase 2 there was an immediate significant (uncorrected) reduction of the heart rate after
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30-60 minutes of probatory tVNS. During the time course of tVNS treatment pulse frequency

tended to increase and diminished again at follow-up 4 weeks after end of treatment. ANOVA
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for the parameter QTc for all time points and for contrast screening/baseline to W24 visit

(end of treatment) displayed near-significant effects with regard to a prolongation of the QTc
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time (see Table 14). Conflicting results regarding this parameter have been found for phase
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1 (see above). Notably, the QTc range remained always below critical levels.

Two further severe adverse events were observed during the time course of the study
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(elective bowel operation and fireworks exposure both requiring hospitalization). Both SAE’s
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were not considered to be influenced or caused by the tVNS application. Further reported
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side effects included a slight tingling sensation, dysesthesia, skin redness and pressure

marks at the stimulation site, painful stimulation, dyspnoea of low intensity and headaches.

Taken together, the tVNS approach can be regarded to be tolerated with little side effects in

a healthy and adult population. In awareness of the function of the vagus nerve on the

conduction system of the heart and the theoretical potential of tVNS to modulate efferent

vagus nerve fibres reflectory after transcutaneous stimulation of the afferent vagus nerve

fibres systematic ECG recordings are recommended in every study of tVNS in order to obtain

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further safety data.

Cognitive testing did not reveal a hint for cognitive side effects of tVNS, which fits with the

literature of implanted VNS (72-75)). A tendency towards improvement of cognitive function

was observed for some tests, but these findings should be interpreted carefully, since

statistical analyses were not controlled for multiple comparisons and this pilot study did not

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include a control group. Thus, if the observed improvement is due to cognition-enhancing

effects or reflects pure training effects is hardly answerable at that moment. Further research

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investigating tVNS as cognitive enhancer may be warranted (76).

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The relatively high drop-out rate in our study demonstrates that a therapeutic tVNS

application of several hours per day over a period of 6 months is apparently only feasible for

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a subgroup of patients. One could assume that a more pronounced therapeutic effect might
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have resulted in higher treatment adherence.

Thus, whereas tVNS alone seems to have no relevant clinical effect on tinnitus, it has been
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shown to be feasible and safe and may hold more promise when combined with other

interventions that have a specific effect on tinnitus-related neuroplastic changes. In addition

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to the combination with specific auditory stimulation also a combination with specific
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cognitive behavioral interventions should be considered.

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Acknowledgement

We want to thank Sandra Pfluegl, Susanne Staudinger, Jarmila Gerxhaliu-Holan, Sylvia

Dorner-Mitschke, Helene Niebling, and Constantin Martin for their assistance in trial

organisation and data handling. For highly appreciated help in ECG acquisition we want to

thank Franziska Mies. Most of all we want to thank our patients for participating in our studies

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and allowing us to use their data for analyses.

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Supplementary materials

Table S1 Clinical Global Impression-Change

Table S2 Raw data and statistics of cognitive testing (phase 2).

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Table S3 Normative values of cognitive testing.

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Figure S1
ECG parameters in phase 2 (N = 14); * = during screening/baseline first ECG recording was

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conducted without stimulation, second ECG was conducted during stimulation after a probatory
stimulation of 30-60 minutes

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Aug;2(4):351-6.
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Alzheimer's disease: a pilot study. J Clin Psychiatry. 2002 Nov;63(11):972-80.

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Table 1 Demographic characteristics at baseline (mean ± sd) (minimum, quartiles, maximum)

(sample size).

Continuous variables are depicted by (mean±sd) (minimum, quartiles, maximum) (sample size). Categorial variables are
depicted by absolute and relative frequencies.

Table 2 Tinnitus related questionnaires and rating scales at baseline.

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Variables are depicted by (mean±sd) (minimum, quartiles, maximum) (sample size).

Table 3 Raw data and statistics for secondary analyses of phase 1 (mean ± sd).

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Table 4 Raw data and statistics for secondary analyses of phase 2 (mean ± sd).

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Table 5 ANOVAS regarding ECG parameters

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Table 6 Frequency of adverse events in the whole study sample (n=50). Absolute numbers of
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reported events are provided.

Figure 3 Patient samples

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Figure 4 Primary Outcome (TQ Score Sc/BL vs. end of treatment).

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Figure S1
ECG parameters in phase 2 (N = 14); * = during screening/baseline first ECG recording was
conducted without stimulation, second ECG was conducted during stimulation after a probatory
stimulation of 30-60 minutes
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Table S1 Clinical Global Impression-Change

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Table S2 Raw data and statistics of cognitive testing (phase 2).

Table S3 Normative values of cognitive testing.

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±sd) (minimum, quartiles, maximum) (sample size).

Table 1. Demographic characteristics (mean±

tVNS Phase 1 tVNS Phase 1 tVNS Phase 1 tVNS Phase 2 tVNS Phase 2 tVNS Phase 2
ITT PP drop outs ITT PP drop outs
laterality
(right/left/ 2/10/12 0/6/7 3/7/1 1/3/20 1/2/12 4/4/1
other)
gender

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(female/ 10/14 7/6 3/8 21/3 12/3 0/9
male)
average 30.5±14.3 31.7±15.6 29±13.4 24.2±13.2 24.0±12.4 24.7±15.8

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hearing loss (5,19,30,43,59) (5,20,31,44,59) (11,17,28,43,49) (6,14,21,36,49) (6,15,22,34,49) (6,9,21,44,46)
in dB (n=22) (n=12) (n=10) (n=21) (n=14) (n=7)

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tinnitus 167.0±134.7 212.9±158.8 112±73 130.4±92.9 113.1±59.1 159.2±131.2
duration (8,67,149,217,479) (15,85,174,383,479) (8,49,114,183,203) (13,54,129,179,374) (13,57,128,171,193) (24,41,129,289,374)
(months) (n=22) (n=12) (n=10) (n=24) (n=15) (n=9)
age at 59.0±10.7 62.3±6.3 55.2±13.6 51.8±9.7 52.8±9.1 50.1±10.9

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presentation (38,53,61,67,73) (52,56,62,67,73) (38,41,59,68,72) (31,46,55,60,67) (36,45,57,60,67) (31,41,54,58,61)

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(years) (n=24) (n=13) (n=11) (n=24) (n=15) (n=9)
44.5±14.3 44.2 ±15.8 45±13.1 40.5±11.7 42.9±9.7 36.3±14.1
age at onset
(15,33,49,55,68) (15,31,51,52,68) (28,33,45,56,66) (19,31,45,49,58) (20,34,47,51,55) (19,25,31,49,58)
(years)
(n=22) (n=12) (n=10) (n=24) (n=15) (n=9)

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Table 1. Tinnitus related questionnaires and rating scales. Variables are depicted by (mean±sd) (minimum, quartiles, maximum) (sample size).

tVNS Phase 1 tVNS Phase 1 tVNS Phase 1 tVNS Phase 2 tVNS Phase 2 tVNS Phase 2
ITT PP drop outs ITT PP drop outs
50.0±19.4 54.7±23.8 43.8±9.5 55.3±21.3 56.4±21 52.9±23.3
THI (22,39,46,55,98) (26,35,49,76,98) (22,,43,44,48,58) (14,40,54,70,96) (14,40,56,74,90) (22,34,52,62,96)
(n=21) (n=12) (n=9) (n=22) (n=15) (n=7)
13.5±5.1 15.1±5.6 11.1±3 14.7±4,3 15.1±4.1 14±4.8

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TBF12 (6,9,13,16,24) (6,10,15,20,24) (7,8,12,14,15) (6,12,14,18,23) (6,13,15,18,23) (7,10,14,18,22)
(n=20) (n=12) (n=8) (n=23) (n=15) (n=8)
48.8±11.7 50.6±14.2 46.7±7.8 52.6±14.8 53.9±15.6 50.4±14.1

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TF (29,42,50,53,75) (32,39,50,61,75) (29,44,47,51,56) (24,40,52,65,75) (24,40,53,66,75) (36,39,46,65,74)
(n=24) (n=13) (n=11) (n=24) (n=15) (n=9)

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10.9±7.2 11.4±9.2 10.1±2 11±8.7 11.4±6.5 10.2±12
BDI (2,6,9,13,33) (2,5,9,16,33) (7,8,11,12,13) (1,6,10,14,41) (2,7,12,14,29) (1,4,6,12,41)
(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)
14.9±2.8 14.6±3.5 15.3±1.5 14.7±2.7 14.4±2.8 15.2±2.5

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WHOQoL
(8,14,15,17,18) (8,11,16,17,18) (14,14,15,17,18) (9,13,15,17,19) (9,13,15,17,19) (9,15,15,17,18)
domain 1

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(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)
14.0±1.0 14±2.4 14±1.3 14.3±2.5 14.2±2.1 14.3±3.3
WHOQoL
(9,13,14,15,17) (9,12,15,15,17) (11,13,14,15,15) (7,13,14,16,18) (11,13,14,16,18) (7,13,15,16,18)
domain 2
(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)

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15.5±3.0 14.8±3.4 16.7±1,9 15.4±2.3 15.2±2.2 15.7±2.4
WHOQoL
(9,14,16,18,20) (9,12,15,18,20) (15,15,16,18,20) (11,14,16,17,19) (12,13,15,17,19) (11,15,16,17,19)
domain 3

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(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)
16.0±2.0 15.8±2.5 16.3±0,9 16.7±1.9 17.3±1.7 15.7±2
WHOQoL

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(13,14,16,17,19) (13,13,16,18,19) (15,16,16,17,18) (12,16,17,18,20) (14,17,18,19,20) (12,15,16,17,19)
domain 4
(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)
6.8±1.9 6.8±2.4 6.7±1 7±1.6 7±1.4 7±2.2
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Loudness (3,6,7,8,10) (3,5,7,8,10) (5,6,7,8,8) (3,6,7,8,10) (4,6,7,8,10) (3,6,8,9,9)
(n=21) (n=12) (n=9) (n=22) (n=15) (n=7)
7.4±2.1 7.5±2.6 7.3±1.2 7.6±1.6 7.6±1.8 7.7±1.1
discomfort (3,7,8,9,10) (3,6,8,10,10) (5,7,7,8,9) (4,7,8,9,10) (4,7,8,9,10) (6,7,8,9,9)
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(n=20) (n=12) (n=8) (n=22) (n=15) (n=7)

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6.8±2.1 7±2.6 6.5±1.3 7±2 6.9±2.1 7.3±1.9

annoyance (3,5,7,8,10) (3,4,7,10,10) (4,6,7,7,8) (3,6,7,8,10) (3,5,7,9,10) (3,7,8,8,9)
(n=20) (n=12) (n=8) (n=23) (n=15) (n=8)
7.5±2.0 7.3±2.2 7.6±1.9 7.9±2 7.5±2.2 8.5±1.3
ignorability (3,6,8,9,10) (3,6,8,9,10) (5,6,8,10,10) (3,6,8,10,10) (3,6,8,10,10) (6,8,9,10,10)
(n=20) (n=12) (n=8) (n=23) (n=15) (n=8)
7.0±2.0 7.1±2.4 6.8±1.2 7±1.9 6.8±2 7.4±1.6
unpleasantness (3,5,7,8,10) (3,5,7,10,10) (5,6,7,8,8,) (3,5,7,8,10) (3,5,7,8,10) (4,7,8,8,9)
(n=20) (n=12) (n=8) (n=23) (n=15) (n=8)
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Table 1. Tinnitus related questionnaires and rating scales. Variables are depicted by (mean±sd) (minimum, quartiles, maximum) (sample size).

tVNS Phase 1 tVNS Phase 1 tVNS Phase 1 tVNS Phase 2 tVNS Phase 2 tVNS Phase 2
ITT PP drop outs ITT PP drop outs
50.0±19.4 54.7±23.8 43.8±9.5 55.3±21.3 56.4±21 52.9±23.3
THI (22,39,46,55,98) (26,35,49,76,98) (22,,43,44,48,58) (14,40,54,70,96) (14,40,56,74,90) (22,34,52,62,96)
(n=21) (n=12) (n=9) (n=22) (n=15) (n=7)
13.5±5.1 15.1±5.6 11.1±3 14.7±4,3 15.1±4.1 14±4.8

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TBF12 (6,9,13,16,24) (6,10,15,20,24) (7,8,12,14,15) (6,12,14,18,23) (6,13,15,18,23) (7,10,14,18,22)
(n=20) (n=12) (n=8) (n=23) (n=15) (n=8)
48.8±11.7 50.6±14.2 46.7±7.8 52.6±14.8 53.9±15.6 50.4±14.1

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TF (29,42,50,53,75) (32,39,50,61,75) (29,44,47,51,56) (24,40,52,65,75) (24,40,53,66,75) (36,39,46,65,74)
(n=24) (n=13) (n=11) (n=24) (n=15) (n=9)

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10.9±7.2 11.4±9.2 10.1±2 11±8.7 11.4±6.5 10.2±12
BDI (2,6,9,13,33) (2,5,9,16,33) (7,8,11,12,13) (1,6,10,14,41) (2,7,12,14,29) (1,4,6,12,41)
(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)
14.9±2.8 14.6±3.5 15.3±1.5 14.7±2.7 14.4±2.8 15.2±2.5

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WHOQoL
(8,14,15,17,18) (8,11,16,17,18) (14,14,15,17,18) (9,13,15,17,19) (9,13,15,17,19) (9,15,15,17,18)
domain 1

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(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)
14.0±1.0 14±2.4 14±1.3 14.3±2.5 14.2±2.1 14.3±3.3
WHOQoL
(9,13,14,15,17) (9,12,15,15,17) (11,13,14,15,15) (7,13,14,16,18) (11,13,14,16,18) (7,13,15,16,18)
domain 2
(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)

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15.5±3.0 14.8±3.4 16.7±1,9 15.4±2.3 15.2±2.2 15.7±2.4
WHOQoL
(9,14,16,18,20) (9,12,15,18,20) (15,15,16,18,20) (11,14,16,17,19) (12,13,15,17,19) (11,15,16,17,19)
domain 3

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(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)
16.0±2.0 15.8±2.5 16.3±0,9 16.7±1.9 17.3±1.7 15.7±2
WHOQoL

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(13,14,16,17,19) (13,13,16,18,19) (15,16,16,17,18) (12,16,17,18,20) (14,17,18,19,20) (12,15,16,17,19)
domain 4
(n=20) (n=12) (n=8) (n=24) (n=15) (n=9)
6.8±1.9 6.8±2.4 6.7±1 7±1.6 7±1.4 7±2.2
EP
Loudness (3,6,7,8,10) (3,5,7,8,10) (5,6,7,8,8) (3,6,7,8,10) (4,6,7,8,10) (3,6,8,9,9)
(n=21) (n=12) (n=9) (n=22) (n=15) (n=7)
7.4±2.1 7.5±2.6 7.3±1.2 7.6±1.6 7.6±1.8 7.7±1.1
discomfort (3,7,8,9,10) (3,6,8,10,10) (5,7,7,8,9) (4,7,8,9,10) (4,7,8,9,10) (6,7,8,9,9)
C

(n=20) (n=12) (n=8) (n=22) (n=15) (n=7)

AC

6.8±2.1 7±2.6 6.5±1.3 7±2 6.9±2.1 7.3±1.9

annoyance (3,5,7,8,10) (3,4,7,10,10) (4,6,7,7,8) (3,6,7,8,10) (3,5,7,9,10) (3,7,8,8,9)
(n=20) (n=12) (n=8) (n=23) (n=15) (n=8)
7.5±2.0 7.3±2.2 7.6±1.9 7.9±2 7.5±2.2 8.5±1.3
ignorability (3,6,8,9,10) (3,6,8,9,10) (5,6,8,10,10) (3,6,8,10,10) (3,6,8,10,10) (6,8,9,10,10)
(n=20) (n=12) (n=8) (n=23) (n=15) (n=8)
7.0±2.0 7.1±2.4 6.8±1.2 7±1.9 6.8±2 7.4±1.6
unpleasantness (3,5,7,8,10) (3,5,7,10,10) (5,6,7,8,8,) (3,5,7,8,10) (3,5,7,8,10) (4,7,8,8,9)
(n=20) (n=12) (n=8) (n=23) (n=15) (n=8)
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Table 3. Raw data and statistics for secondary analyses of phase 1 (mean±sd).

study end
Sc/BL week 2 week 4 week 8 visit F df p

THI (n=21) 50.0±19.4 50.4±19.7 48.2±20.7 48.5±21.3 49.4±21.8 0.769 4,80 0.548

TBF-12 (n=20) 13.5±5.1 13.3±5.7 12.9±5.5 13.0±5.7 13.3±5.7 0.667 4,76 0.617

TQ (n=24) 48.8±11.7 46.3±12.8 45.8±12.9 46.0±13.2 45.2±14.8 3.348 4,92 0.013

PT
BDI (n=20) 10.9±7.2 10.0±7.2 9.4±6.9 9.9±7.9 8.8±6.0 4.870 4,76 0.002

WHOQOL 1 (n=20) 14.9±2.8 14.62.8 14.7±2.6 14.7±2.8 15.1±2.7 1.851 4,76 0.128

RI
WHOQOL 2 (n=20) 14.0±2.0 14.4±2.4 14.6±2.4 14.5±2.7 14.5±2.4 1.994 4,76 0.104

SC
WHOQOL 3 (n=20) 15.5±3.0 15.2±3.4 15.4±3.0 15.3±3.3 15.3±3.3 0.355 4,76 0.840

WHOQOL 4 (n=20) 16.0±2.0 16.0±2.2 16.4±2.0 16.0±2.5 16.4±2.1 0.871 4,76 0.485

U
Loudness (n=21) 6.8±1.9 6.1±2.2 6.5±2.0 6.7±2.2 6.9±1.9 1.529 4,80 0.202

Discomfort (n=20) 7.4±2.1 6.8±2.5 7.0±2.1 7.1±2.2 7.1±1.8 0.791 4,76 0.535
AN
Annoyance (n=20) 6.8±2.1 6.7±2.4 6.7±2.4 6.8±2.5 7.1±2.2 0.419 4,76 0.794

Ignorability (n=20) 7.5±2.0 6.9±2.4 6.7±2.5 6.8±2.5 7.0±2.1 1.009 4,76 0.408
M

Unpleasantness (n=20) 7.0±2.0 6.9±2.3 6.7±2.2 6.9±2.4 7.1±2.2 0.457 4,76 0.767
D
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Table 4. Raw data and statistics for secondary analyses of phase 2 (mean±sd).

Sc/BL week 2 week 4 week 8 week 12 week 24 week 28 F df p

THI (n=22) 55.3±21.3 58.0±21.5 56.8±22.2 56.8±22.7 58.2±23.5 58.0±25.3 57.0±26.2 0.646 6,126 0.693

TBF-12
14.7±4.3 15.2±4.7 14.9±4.7 15.2±4.6 15.6±4.7 15.3±4.6 15.0±5.1 0.770 6,132 0.595
(n=23)

TQ (n=24) 52.6±14.8 50.5±16.3 49.4±16.3 49.9±16.2 51.1±16.4 49.8±19.0 49.8±19.5 1.286 6,138 0.268

PT
BDI (n=24) 11.0±8.8 11.0±8.7 10.4±8.9 10.8±8.3 11.1±8.9 11.1±9.4 11.0±9.7 0.429 6,138 0.859

WHOQOL 1
14.7±2.7 14.4±2.8 14.4±2.9 14.5±3.0 14.4±2.9 14.1±3.1 14.3±2.8 0.909 6,138 0.490

RI
(n=24)

WHOQOL 2
14.3±2.5 13.8±2.5 14.0±2.5 13.8±2.7 13.8±2.9 13.8±2.9 13.8±2.7 1.515 6,138 0.177
(n=20)

SC
WHOQOL 3
15.4±2.3 15.7±2.3 15.3±2.3 15.2±2.0 15.3±2.5 15.1±2.6 15.0±2.2 1.628 6,138 0.144
(n=20)

U
WHOQOL 4
16.7±1.9 16.6±1.8 16.6±1.8 16.3±1.9 16.5±2.0 16.4±1.7 16.4±1.8 0.944 6,138 0.466
(n=20)
AN
Loudness
7.0±1.6 7.2±1.7 7.4±1.4 7.3±1.6 7.5±1.4 7.3±2.0 7.1±2.0 0.955 6,126 0.458
(n=22)

Discomfort
7.6±1.6 7.6±1.4 7.6±1.4 7.5±1.7 7.9±1.3 7.5±2.0 7.2±2.1 1.003 6,126 0.427
M

(n=22)

Annoyance
7.0±2.0 7.2±1.7 7.6±1.3 7.5±1.7 7.8±1.5 7.4±2.1 7.3±2.2 1.618 6,132 0.147
(n=23)
D

Ignorability
7.9±2.0 7.7±2.2 8.1±1.8 7.9±1.9 7.9±2.2 7.4±2.5 7.1±2.3 1.354 6,132 0.238
TE

(n=23)

Unpleasant-
7.1±1.8 7.2±1.9 7.8±1.3 7.8±1.3 7.9±1.2 7.6±1.8 7.4±2.0 2.054 6,126 0.063
ness(n=22)
C EP
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F (df) p-value partial F (df) p-value partial eta2

eta2
All time points (N=14)

PT
HF 1.967 (3.69, 47.97) .119 .131
PQ .307 (7, 91) .949 .023

RI
QRS .836 (7,91) .560 .060
QTc 2.219 (3.951, 51.358) .081 .146
Scr/BL: prestim – during stimulation (N = 14) Scr/BL: prestim – during stimulation (N = 26)

SC
HF 12.056 (1, 13) .004 .481 5.059 (1,25) .034 .168

U
PQ .290 (1, 13) .600 .022 .510 (1,25) .482 .020
QRS .476 (1, 13) .502 .035 .000 (1,25) 1.000 .000

AN
QTc .032 (1, 13) .861 .002 .528 (1,25) .474 .021
Scr/BL (prestim) – week 24 (N = 14) Scr/BL (prestim) – week 24 (N = 17)

M
HF 2.906 (1, 13) .112 .183 5.739 (1, 16) .029 .264
PQ .322 (1, 13) .580 .024 .685 (1, 16) .420 .041

D
QRS 3.090 (1, 13) .102 .192 2.482 (1, 16) .135 .134
QTc 4.191 (1, 13) .061 .244 3.987 (1, 16) .063 .199

TE
C EP
AC
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Adverse event Absolute number of patients (n=50)
Dysesthesia 7
Redness/pressure mark 7
Dyspnoe 5
Local pain 4
Headache 4
Chest pain 3
Voice alteration / hoarseness 2
Nausea 2
Arrhythmia 2

PT
Dizziness 1
Transient subjective hearing impairment 1
Neck pain 1

RI
Numbness 1

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End of
week 2 week 4 week 8 Week 12 week 24 week 28
phase 1

Original phase 1
sample (better/equal/worse/ 3/14/3/4 2/9/1/12 0/1/3/20 2/13/3/6 - - -
missing values)

Locf
sample 3/14/3/4 3/15/2/4 3/13/4/4 3/18/3/0 - - -

PT
Original phase 2
sample (better/equal/worse/ 2/20/0/2 2/19/1/2 1/15/1/7 1/14/4/5 3/9/5/7 3/14/2/5

RI
missing values)

Locf

SC
sample 2/20/0/2 2/21/1/0 1/22/1/0 1/19/4/0 3/16/5/0 3/18/3/0

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Table S2. Raw data and statistics of cognitive testing (only available for phase 2).

baseline week 12 statistics

mean n sd mean n sd t df p
tonic alertness median reaction
319.57 21 139.423 300.33 21 106.645 1.918 20 .070
time (ms)
phasic alertness median reaction
316.14 21 125.956 296.90 21 76.049 1.152 20 .263
time (ms)
working memory median reaction

PT
581.11 19 192.017 560.79 19 144.753 .399 18 .694
time (ms)
working memory errors
3.86 21 5.738 3.43 21 4.945 .585 20 .565
(absolute values)

RI
working memory omissions
3.38 21 4.213 2.38 21 3.598 2.070 20 .052
(absolute values)
divided attention errors
1.71 21 2.686 1.67 21 2.633 .134 20 .895
(absolute values)

SC
divided attention omissions
5.24 21 9.544 1.05 21 1.359 2.028 20 .056
(absolute values)
baseline week 24 statistics

U
mean n sd mean n sd t df p
tonic alertness median reaction
AN
319.57 21 139.423 210.14 21 136.730 3.161 20 .005
time (ms)
phasic alertness median reaction
317.80 15 141.203 263.40 15 52.362 1.740 14 .104
time (ms)
working memory median reaction
M

578.00 14 206.934 555.86 14 132.486 .485 13 .635

time (ms)
working memory errors
4.33 15 6.433 2.73 15 5.120 1.349 14 .199
(absolute values)
D

working memory omissions

3.40 15 4.273 1.47 15 1.685 2.360 14 .033
(absolute values)
divided attention errors
TE

2.13 16 2.941 1.31 16 1.991 1.062 15 .305

(absolute values)
divided attention omissions
4.19 16 6.645 1.13 16 1.857 1.851 15 .084
(absolute values)
EP

week 12 week 24 statistics

mean n sd mean n sd t df p
tonic alertness median reaction
300.33 21 106.645 210.14 21 136.730 2.791 20 .011
C

time (ms)
phasic alertness median reaction
287.47 15 75.762 263.40 15 52.362 2.185 14 .046
AC

time (ms)
working memory median reaction
585.93 15 148.124 541.20 15 139.719 1.472 14 .163
time (ms)
working memory errors
3.67 15 4.850 2.73 15 5.120 .969 14 .349
(absolute values)
working memory omissions
1.87 15 2.386 1.47 15 1.685 1.000 14 .334
(absolute values)
divided attention errors
2.13 16 2.872 1.31 16 1.991 1.338 15 .201
(absolute values)
divided attention omissions
1.19 16 1.471 1.13 16 1.857 .324 15 .751
(absolute values)
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Table S3. Normative values of cognitive testing.

phase 1 phase 2

% %
baseline within outside within outside
within within
tonic alertness median
10 1 91 21 3 88
reaction time (ms)
phasic alertness median

PT
10 0 100 22 2 92
reaction time (ms)
working memory median
11 0 100 23 0 100
reaction time (ms)
working memory errors

RI
10 1 91 22 2 92
(absolute values)
working memory omissions
10 1 91 19 5 79
(absolute values)

SC
divided attention errors
11 0 100 24 0 100
(absolute values)
divided attention omissions
10 1 91 20 4 83
(absolute values)

U
% %
week 12 within outside within outside
within within
AN
tonic alertness median
- - - 20 1 95
reaction time (ms)
phasic alertness median
- - - 19 2 90
reaction time (ms)
M

working memory median

- - - 20 0 100
reaction time (ms)
working memory errors
- - - 21 0 100
(absolute values)
D

working memory omissions

- - - 19 2 90
(absolute values)
TE

divided attention errors

- - - 21 0 100
(absolute values)
divided attention omissions
- - - 21 0 100
(absolute values)
EP

% %
week 24 within outside within outside
within within
tonic alertness median
- - - 20 1 95
C

reaction time (ms)

phasic alertness median
- - - 15 0 100
reaction time (ms)
AC

working memory median

- - - 15 0 100
reaction time (ms)
working memory errors
- - - 14 1 93
(absolute values)
working memory omissions
- - - 15 0 100
(absolute values)
divided attention errors
- - - 16 0 100
(absolute values)
divided attention omissions
- - - 16 0 100
(absolute values)